Topiramate is an FDA approved anticonvulsant drug used as a monotherapy or an adjuvant therapy to treat a variety of forms of epilepsy (see Physician's Desk Reference, 56th ed., 2590-2595 (2002); disclosed in U.S. Pat. No. 4,513,006). Topiramate is used to prevent both partial onset and generalized seizures and is approved to treat simple partial seizures, complex partial seizures, and generalized tonic-clonic seizures in both children and adults. It is also indicated for treatment of Lennox-Gastaut syndrome (a disorder that causes seizures and developmental delays) in children.
There are three classifications of partial seizures: simple, complex, and secondarily generalized. A simple partial seizure usually manifests as jerking or shaking in one area of the body, which may progress to other areas. Simple partial seizures may also manifest with somatosensory, visual, auditory, olfactory, autonomic (sweating, pupillary dilation, epigastric rising), or psychiatric symptoms. In the case of complex partial seizures, the patient's consciousness may also be impaired. Patients experiencing a complex partial seizure will often exhibit a blank stare followed by automatism, which may include lip smacking, chewing, picking at clothing, or purposeless walking. Secondarily generalized seizures can evolve directly from simple partial or complex partial seizures, or progress from simple partial to complex partial to generalized (Leppik I E. Contemporary Diagnosis and Management of the Patient with Epilepsy. 4th Ed., Newtown, Pa.: Handbooks in Health Care Co (1999)).
Generalized seizures involve a loss of consciousness and may or may not be convulsive. Absence seizures (formerly called “petit mal”) may be typical or atypical. The symptoms of typical absence seizures include a blank stare, eye blinking, and in some instances automatisms, and the patient may experience increased or decreased tone. These brief seizures tend to occur in groups and can occur 50 to 100 times in a day (Leppik I E. Contemporary Diagnosis and Management of the Patient with Epilepsy. 4th Ed., Newtown, Pa.: Handbooks in Health Care Co (1999)). Atypical absence seizures begin and end less abruptly than the typical absence seizures, but last longer and result in more pronounced changes in tone.
Myoclonic seizures manifest with quick, involuntary muscle jerks, which may be isolated to one part of the body or involve the entire body. Myoclonic seizures may accompany other generalized seizures and are common to specific epilepsy syndromes. Tonic seizures are generally associated with other epileptic syndromes and typically last less than a minute. Tonic seizures involve violent spasm or stiffening, and in many instances the lower extremities are extended and the upper extremities are flexed. In addition, the patient may turn the head or eyes to one side. Clonic seizures, most common in neonates and children, also exhibit repetitive muscular jerks but at a slower rate, and while clonic seizures can last as long as several minutes, brief episodes are more common (Leppik I E. Contemporary Diagnosis and Management of the Patient with Epilepsy. 4th Ed., Newtown, Pa.: Handbooks in Health Care Co (1999)).
Generalized tonic-clonic seizures (also called “grand mal”) can occur at any age but are rare in very young infants (Morton et al., “Diagnosis and treatment of epilepsy in children and adolescents”, Drugs 51: 399-414 (1996)). The seizures start with a sudden-onset tonic phase, typically lasting less than a minute, with all of the skeletal muscles contracting at once causing the patient to fall stiffly. In addition, the patient's diaphragm and chest muscles contract, forcing out air in a sigh or “epileptic cry.” During the clonic phase, the patient may clench the jaws, biting the inside of the cheek or side of the tongue with the molars, and consciousness may not return for 10 to 15 minutes. The episode may result in feeling confusion, fatigue, and headache, which can last several hours to several days (Leppik I E. Contemporary Diagnosis and Management of the Patient with Epilepsy. 4th Ed., Newtown, Pa.: Handbooks in Health Care Co (1999)).
Atonic seizures result in a sudden loss of postural tone, causing the patient to fall. After a few seconds, the patient regains full consciousness. Atonic seizures are commonly associated with other seizure types and are common in Lennox-Gastaut syndrome (Leppik I E. Contemporary Diagnosis and Management of the Patient with Epilepsy. 4th Ed., Newtown, Pa.: Handbooks in Health Care Co (1999)).
Other epileptic conditions include juvenile myoclonic epilepsy and Lennox-Gastaut syndrome. Juvenile myoclonic epilepsy is a generalized, idiopathic epileptic syndrome, often exhibiting three seizure types: myoclonic, absence, and generalized tonic-clonic. Lennox-Gastaut syndrome may be symptomatic (brain lesion identified) or cryptogenic (brain lesion assumed), and the generalized syndrome may include atypical absence, tonic, atonic, and tonic-clonic seizures. Patients suffering from Lennox-Gastaut syndrome also have varying degrees of psychomotor retardation (Leppik I E. Contemporary Diagnosis and Management of the Patient with Epilepsy. 4th Ed., Newtown, Pa.: Handbooks in Health Care Co (1999); and Beaumanoir et al., “The Lennox-Gastaut syndrome”, In: Roger et al., “Epileptic Syndromes in Infancy, Childhood, and Adolescence”, 2.sup.nd Ed., London, England: John Libby, pp. 231-244 (1992)).
Memory impairment, mental slowing and attention deficits are the most frequently reported cognitive disorders in people with epilepsy and sometimes patients can find these cognitive consequences more debilitating than the actual seizures. Cognitive deficits in epilepsy are likely to be attributed to three key factors: the syndrome itself, the seizures, and the effect of the antiepileptic drug used for seizure control. The cognitive side effects of anti-epileptic drugs are particularly important in cognitively vulnerable populations such as children and elderly subjects. For example, side effects that manifest as minor cognitive impairments when observed in adults can cause extensive learning and cognition difficulties in children.
In addition to its use as an anticonvulsant, topiramate is most frequently prescribed for migraine prophylaxis [Brandes, et al., JAMA. 291 (8): 965-73 (2004); Silberstein et al., Arch Neurol. 61(4):490-5 (2004); Storey et al., Headache. 41(10):968-75 (2001); Mathew et al., Headache. 42(8):796-803 (2002); Diener et al., J. Neurol. 251(8):943-50 (2004); D'Amico et al Neurol Sci S130-S133 (2005); Storey J L et al. Neurology. (54) A267-A268 (2000); Edwards et al. Cephalalgia 20: S16 (2000]. Migraine is a severe form of recurrent headache typically accompanied by dizziness, nausea, vomiting or extreme sensitivity to light and sound. The classic migraine type may begin with aura, which consists of episodes of well-defined, transient focal neurological dysfunction that develops over the course of minutes and may last up to an hour.
Migraine treatment has progressed greatly over the last decade but unfortunately, prophylactic treatment of migraine has lagged behind acute care treatment. Beta-adrenergic blockers, calcium channel antagonists, antidepressant medications, and antiepileptic drugs (AEDs) have primary indications for other medical conditions but are commonly used for the prophylactic pharmacotherapy of migraine. For migraine prophylaxis preventive medications are typically selected by efficacy, adverse reactions, patient preference, co-occurrence of illness, and cost. The overall goals of prophylactic migraine therapy are to reduce the frequency and severity of migraine attacks, to make acute migraine attacks more responsive to abortive therapy and to improve the quality of life for patients. Many classes of drugs have been used but the prophylactic pharmacotherapy of migraine is less than satisfactory, because of poor efficacy, associated unacceptable side effects, tachyphylaxis and drug interactions.
Topiramate has been approved by FDA for migraine prophylaxis. Topiramate has numerous effects on the central nervous system, including neuronal excitability blockade and on excitatory amino acids, which are considered to be involved in the pathophysiology of migraine. Due to these effects, topiramate has been used for preventive management of chronic and intractable migraine.
Topiramate has been used by psychiatrists to treat bipolar disorder, although it is not FDA approved for this purpose. Because it is also one of only three AEDs that have a statistically proven propensity to induce weight loss, the drug has been investigated for use in treatment of obesity, especially to aid in the reduction of binge eating (McElroy, et al., Am J. Psychiatry. 160(2):255-61 (2003)). Topiramate is useful for neuropathic pain relief. In some groups of patients, diabetics for example, the potential of weight loss is desirable and may therefore be a major reason for using this medication for the treatment of diabetic neuropathic pain.
Other investigational uses of topiramate include treating alcoholism (Johnson, et al., Lancet 361(9370):1677-85 (2003)), cocaine and tobacco addiction (Sofuoglu, et al., Psychopharmacology 184(3-4): 645-51 (2006)), sleep disorders (Webber, Am J Psychiatry 159:872-873 (2002)), sleep-related eating disorders (Winkelman, Sleep Med. 4(3):243-246 (2003)), Post traumatic stress disorder (Berlant, J Clin Psychiatry 62 Suppl 17:60-63 (2001)), depression (Carpenter, et al., J Affect Disord. 69(1-3):251-255 (2002)), and cluster headache (Lainez, Headache. 43(7):784-9 (2003)).
For the treatment of epilepsy, the recommended dosage of Topamax® is 400 mg/day typically taken in two divided doses (Physicians' Desk Reference, Thompson Healthcare, 56th Ed., pp. 2590-2595 (2002)). Lower doses than 400 mg/day (50-200 mg/day) are typically used for treating cluster headache and migraine prevention in non-epileptic subjects (U.S. Pat. No. 6,503,884, D'Amico., D et. al. Neurological Sciences 26, p 130, supplement 2, 2005, and Mosek, A et. al. Jr. of Headache and Pain 6, p 77, 2005). Topiramate pharmacokinetics are linear, producing a dose-proportional increase in blood plasma concentration levels with increased dosing. Further, topiramate treatment has shown no evidence of patients developing drug tolerance with prolonged treatment over time. Following oral administration of an immediate release dosage form, topiramate is rapidly absorbed with peak plasma drug concentrations noted in approximately 2 hours. The mean elimination half life is about 21 hours. Topiramate pharmacokinetics are also not significantly affected by food.
The currently marketed immediate release topiramate formulation (Topamax®) is not ideal as it is associated with poor patient compliance as well as treatment-emergent side effects that lead to poor patient tolerance. The pharmacokinetics of the Topamax lead to high Cmax-related adverse effects including paresthesia, drowsiness, nausea, and vomiting, weight loss, ataxia, taste perversion and renal calculi. The most frequently reported adverse effects include behavioral and cognitive difficulties with an incidence of almost 50% in one retrospective review of 174 patients ((Kellet et al. J. Neurol. Neurosurg and Psych. 1999; 66:759-763). Similar results were also observed in various other studies (Thompson et al. J. Neurol. Neurosurg and Psych. 2000; 69:634-641 and Meador et al. Neurology 2005; 64: 2108-2114). Decline in verbal frequency, attention, processing speed and working memory were seen for Topamax in another adjunctive study of patients with epilepsy (Lee et al. Epilepsia 2003; 44: 339-347). The negative cognition effects of Topamax are especially important to those who require maximal cognitive efficiency in their jobs and daily activities.
The time it takes for topiramate to reach peak plasma levels (i.e., about two hours) also limits its effective use in the treatment of some conditions, such as neuropathic pain. Therefore, improved dosage forms of topiramate are needed in order to increase the safety, effectiveness, and utility of the compound.